Dietary Factors and Risk of Chronic Obstructive Pulmonary Disease: a Systemic Review and Meta-Analysis

Background: The relationship between dietary pattern and the risk of chronic obstructive pulmonary disease (COPD) has been described; however, the exclusive role of dietary factors remains controversial. Hence, we conducted this systematic meta-analysis to clarify the role of some nutrients and antioxidant vitamins in the risk of COPD. Materials and Methods: PubMed, Embase, and Scopus databases were searched for studies evaluating the associations between COPD outcome measures, symptoms, and mortality, and intake of fruits and vegetables, fiber, fish, n-3 or n-6 fatty acids, and antioxidant vitamins in adults. The random-effect model meta-analyses were used to pool the results. Results: Ten cohort, six case-control, and 20 cross-sectional studies were identified. The pooled relative risks (RRs) of the COPD and confidence intervals (CIs) for the highest intake group compared with the lowest intake group were 0.74 (95% CI: 0.65–0.85) for fruit, 0.65 (95% CI: 0.55–0.78) for dietary fiber, 0.71 (95% CI: 0.58–0.85) for fish, and 0.89 (95% CI: 0.76–0.99) for vitamin C. No association was observed between the risk of COPD and the intake of vegetables, n-3 fatty acids, vitamin E, and β-carotene; however, it was associated with n-6 fatty acids 1.06 (95% CI: 0.87–1.30). Conclusion: The results suggested that a higher intake of fruits, probably dietary fiber, and fish reduce the risk of COPD.


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a global public health problem and is a major cause of morbidity and mortality in developed and developing countries; according to estimations, it is the eighth cause of disabilityadjusted life-years (DALYs) in 2016 in all age groups, and with an aging population, COPD prevalence is believed to increase (1)(2)(3)(4). COPD is a preventable disease characterized by progressive airflow limitation, which only can be partially reversible. Smoking is the principal cause of COPD, but not all smokers develop the disease (2). Besides genetic factors, environmental exposures and dietary habits have been suggested as etiological factors for the risk of COPD (5)(6)(7). Additionally, the increased oxidative burden, as a major source in the pathogenesis of COPD, plays a critical role in lung injury and airway remodeling.
One of the primary treatment targets of COPD is an improvement in the quality of life. In this regard, evidence highlights the importance of dietary modifications as TANAFFOS antioxidant sources in the prevention and management of COPD (8,9).
Several studies have suggested that specific foods and dietary supplements may be beneficial in COPD prevention and management (10,11). Specific antioxidants (e.g., vitamins C and E), as well as foods rich in antioxidants (e.g., fruit and vegetables), appear to modulate lung function positively, airway damage, and COPD development and symptoms (12,13). A recent review reported that a high intake of dietary fiber is associated with reduced COPD risk (14). In addition, fish and fatty acid consumption have both been directly correlated with respiratory symptoms of COPD (15).
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), appear to have antiinflammatory effects; however, there is contradictory evidence regarding the inverse association between intake of n-3 PUFAs and the risk of COPD and mortality (16).
These findings have not yet been quantified in a comprehensive review or pooled using meta-analysis techniques. A recent review reviewed randomized controlled trials (RCTs) on the relationship between dietary pattern (nutritional supplementation) and the risk of COPD, in which no relationship was found between these two factors (17,18). Thus, this study systematically investigated the association between some nutrients, including fruits, vegetables, fatty acids, and the antioxidant vitamins and the risk of COPD.

MATERIALS AND METHODS
Both the systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting the current study (19).

Search strategy and eligibility criteria
We searched PubMed (Medline), Embase, and Scopus databases for studies published in English from January 1990 to November 2018 on the associations between COPD outcomes and the intake of fish, fruits and vegetables, fiber, fatty acids (n-3 and n-6), and antioxidant vitamins (C, E, and β-carotene) in adults. Additional studies were identified by searching the reference list of the retrieved articles and the Science Citation Index manually.
The Critical Appraisal Skills Programme (CASP) was used to critically appraise the included observational studies (20).

Data extraction
The following information was extracted from the
The pooled analysis of seven studies showed a 26% reduction in the risk of COPD (symptom and outcomes) that was significantly associated with high fruit intake without heterogeneity ( studies reporting an association between fruits intake and COPD outcomes (22,28,30,32,54) or three studies regarding symptoms (25,32,56), there were no changes in the pooled effect estimates as displayed in Table 2. Metaanalysis on the association between COPD mortality and higher fruit consumption also showed a significant reduction in the risk of COPD mortality (RR=0.53; 95% CI: 0.39-0.74; I2: 0.0%; heterogeneity P-value: 0.65) ( Table 2).
When the highest intake category of vegetables was compared with the lowest intake category, the pooled RR was null for the associated COPD symptoms and outcomes (  (21,24). In addition, there was no association between COPD risk and the total intake of fruits and vegetables ( Table 2).
A meta-analysis of the relationship between dietary fiber consumption and COPD risk (symptoms and outcomes), showed a 35% reduction in COPD risk (Table 2 and Fig. 2c). In this regard, stratification by study type Among six studies investigating n-3 fatty acids, there were no associations between their high intake and risk of either COPD outcomes alone or both COPD symptoms and outcomes ( CI: 0.72-1.0; I2: 60%; heterogeneity P-value: 0.04) ( Table 2 and Fig. 2d). The detailed analysis based on COPD symptoms, outcomes, or mortality is shown in Table 2.
High intake of β-carotene was not associated with a risk of COPD in either the pooled analysis (  (44,45). In addition, a high intake of vitamin C was associated with a reduced risk of COPD according to six studies, yet with a substantial heterogeneity (   1960 1984-1985 1958-1964 1958-1964 1993-1998 1984-2000 1984-1998 2001-2006 1998-2012 1998-2012 Sample    74 (0.65, 0.85)   0.88 (0.72, 1.07 (57). It has been reported that increased oxidative stress is a potential pathogenic factor for COPD (58). Therefore, it is suggested that the negative association between fruits and vegetables intake and COPD-related outcomes might be partly due to the antioxidant properties of these nutrients, such as vitamin C, flavonoids, and carotenoids (26,59). Previous studies have supported the protective effect of flavonoids on COPD symptoms (25,60). These compounds may protect against oxidant-mediated damage that leads to COPD (27).
Although these antioxidants can be found in almost all fruits and vegetables, fruits have higher levels of antioxidants (61). This difference suggests a possible explanation for the observation that the association between COPD and high fruit intake was stronger than high vegetable intake.
Notably, longitudinal studies support the negative association between fiber intake and COPD that can be related to anti-inflammatory properties of dietary fiber (26). In agreement with our findings, some prospective studies supported strong associations between long-term increased fruits and fiber intake and health conditions (62).
Fiber intake is associated with lower levels of C-reactive protein and pro-inflammatory cytokines and higher levels of some anti-inflammatory cytokines, such as adiponectin (63,64 The findings showed that vitamin E reduced the risk of COPD symptoms; however, no associations were found in pooled analysis of both symptoms and outcomes. This antioxidant vitamin may protect the lungs from oxidative damage caused by smoking or air pollution. Vitamin E is a free radical scavenger found in tissue membrane, as well as intracellular and extracellular lung fluids. In extracellular lung fluid and lipid membranes, vitamin E converts oxygen radicals and lipid peroxyl radicals to less reactive forms (67). A negative relationship was also observed between the intake of vitamin C and the risk of COPD. In this study, the interaction between these vitamins had not been investigated, and their synergic effects had not been quantified. Additionally, considering the biological interaction between vitamins C and E, the extent to which the protective effect of vitamin E is related to that of vitamin C is unresolved (68).
The results of the meta-analysis did not support the association between the intake of unsaturated fatty acids (n-3 and n-6 fatty acids) and the risk of COPD.
Observational studies have been conducted based on the hypothesis that n-6 fatty acids could stimulate the production of pro-inflammatory eicosanoids, while antiinflammatory n-3 fatty acids might promote the metabolism of these molecules into less biologically active eicosanoids, such as leukotriene B5 (69).
The current study had some limitations. Some analyses were based on only two studies, and few prospective studies were included. Furthermore, the null findings suggest that the effect of any individual nutrient in reducing the risk of COPD may be too small to detect; however, when several nutrients are consumed together, the cumulative effect may be sufficient for detection (17).
Although some articles were cross-sectional studies, but the cohort study, which included in the pooled analysis studies, exhibited logical outcomes. Another limitation of this meta-analysis was the heterogeneity identified in some of the pooled analyses, which may be attributed to the sample sizes, small number of the studies included, or the distribution of effective modifiers that were not investigated in the primary studies and could not be detected. Studying an overall dietary approach rather than specific foods or nutrients is effective in investigating the association between dietary patterns and diseases more comprehensively. However, this study revealed a strong negative association with taking fruits and the risk of COPD (70).
Our results support nutritional interventions encouraging taking fruits, and probably fish, and dietary fiber, which can reduce the risk of COPD outcomes and symptoms significantly.